Indium fluorogermanate,in2(gef6)3



United States Patent 3,494,732 INDIUM FLUOROGERMANATE, In (GeF Joseph C. Muhler, Indianapolis, Ind., assignor to Indiana University Foundation, Bloomington, 11111., a not-forprofit corporation of Indiana No Drawing. Filed Jan. 15, 1968, Ser. No. 697,618 Int. Cl. C01g 15/00, 17/04 US. C]. 2351 1 Claim ABSTRACT OF THE DISCLOSURE A new composition of matter comprising indium, germanium, and fluorine, namely, indium fluorogermanate, In (GeF has been discovered. This compound when incorporated into oral compositions for caries prophylaxis (e.g., as a constituent of a dentifrice or prophylaxis paste) has demonstrated substantial utility as a topical anticariogenic agent.

BACKGROUND OF THE INVENTION Field of the invention Description of the prior art It is commonly recognized that the presence of small (i.e., about 1.0 ig/ml.) amounts of fluoride ion in drinking water has a significant effect in reducing the incidence of dental caries in humans. Sodium fluoride, as an example, has been introduced into the public water supplies in a number of communities with good results. This method of providing fluoride is not feasible, however, where drinking water is obtained from small, private fluoride deficient sources (such as individual wells, etc.) rather than from fluoridated (naturally or fortified) common public sources. Further, the addition to common public sources is not always accepted or permitted, nor i it completely effective.

Topical applications of aqueous fluoride solutions by dentists or dental hygienists provide an excellent measure of protection against dental caries. Various fluoride compounds have been employed for this purpose, including sodium fluoride and stannous fluoride. Likewise, dentifrices and mouthwash compositions comprising various fluoride compounds are known to exhibit anticariogenic effectiveness.

Although effective dental caries protection has been obtained through the use of the aforementioned fluoride compounds, occasional side effects have been experienced with certain of the known anticariogenic agents, particularly certain stannous ion containing salts. For example, a brownish pigmentation of certain cariou lesions has been experienced after topical solutions of anticariogenic agents containing the stannous ion have been applied to the teeth when the teeth are not properly cleaned with a toothbrush following such treatment. Although the pigmentation of carious lesions is not necessarily undesirable 3,494,732 Patented Feb. 10, 1970 from a physiological standpoint, nevertheless, for aesthetic reasons, it would be desirable to provide an equally effective or superior anticariogenic agent that does not pigment the carious enamel, but which has similar dental caries arrestment potential.

Moreover, the utility of certain of the prior art anticariogenic agents has been limited by the extent of th ir solubility in an aqueous media. For example, sodium fluoride (NaF) is only soluble to the extent of about 4% in water. Solubility can, of course, limit the quantity of anticariogenic ions provided by an agent that is available for reaction with the tooth surface. The relative insolubility of certain of the prior art anticariogenic agents limits the value of the same for use in prophylactic paste compositions since the volume of water is prophylactic pastes is substantially limited.

Finally, certain of the known prior art anticariogenic agents have been relatively unstable in aqueous solutions. For example, stannous ions are subject to oxidation and hydrolysis and, for that reason, stannous containing compositions must ordinarily be in freshly prepared form or must be used in conjunction with complexing anions in order to obtain its optimal anticariogenic effect.

The anticariogenic effectiveness of the prior art agents has been limited by the aforementioned problems. Moreover, the utility of these agents has been somewhat limited by the relative toxicity of these agents. The percentage of these agents contained in oral compositions must be carefully maintained at a relatively low level to prevent chronic toxicity of the agents in the body. Thus, maxi-' mum anticariogenic effectiveness by the use of these agents cannot be obtained.

Accordingly, a primary object of the present invention is to provide oral compositions for dental caries prophylaxis comprising an anticariogenic agent exhibiting a high level of anticariogenic effectiveness.

Another object of the present invention is to provide an anticariogenic agent of the character described that demonstrate substantial ionic stability.

Another object of the present invention is to provide an anticariogenic agent of the character described that is substantially non-toxic for human use.

Another object of the present invention is to provide an anticariogenic agent of the character described that does not pigment or discolor the oral hard tissues during or subsequent to use.

Another object of the present invention is to provide an anticariogenic agent of the character described that can be used at relatively high concentrations relative to known anticariogenic fluoride-containing compounds.

SUMMARY OF THE INVENTION In accordance with the present invention, it has been found that new and more effective oral compositions for caries prophylaxis may be obtained by utilizing a new composition of matter, indium fluorogermanate,

as an anticariogenic agent. Such oral compositions (which may take the form of dentifrices, prophylaxis pastes, topical solutions, and mouthwashes) comprise from about 0.01 to 50% by weight of the indium fiuorogermanate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The foregoing and other objects, advantages, and features of the present invention will hereinafter appear, and,

for the purposes of illustration, but not of limitation, exemplary embodiments of the subject invention are hereinafter described in detail.

Indium fluorogermanate, In (GeF is a fine white crystalline powder. The material is thermally stable to 170 0., at which time an as yet unidentified change occurs. The second material is stable to 600 C. at which temperature a second change occurs. At no time during the heating do identifiable oxides appear, though it is only reasonable to conclude that these are the end products.

PREPARATION AND PROPERTIES Indium fluorogermanate may conveniently be repared by co-precipitation or fusion methods. To prepare this compound by co-precipitation, a total of 11.92 g. of ammonium fluorogermanate, (NH GeF are completely dissolved in 20 ml. of redistilled water. In a separate container 8.14 g. of indium chloride, InCl are dissolved in 20 ml. of redistilled water. As the two solutions are mixed, a mildly exothermic reaction occurs. The product,

1112 GeF 3 is obtained by evaporation. The product is heated at 85 C. to volatilize the NH Cl formed. In (GeF is formed in about 90% yield. The chemical equation for the coprecipitation reaction is as follows:

In preparing indium fluorogermanate by a fusion method, 5.96 g. of (NH GeF and 4.07 g. of InCl are admixed in a platinum crucible. The mixture is heated over an open flame until a molten state is reached (a white smoke escapes during the final heating). The product is dissolved in boiling water, filtered, and evaporated in an oven at 85 C. to volatilize the NH C1. The fusion reaction occurs in accordance with the same equation given above for the co-precipitation method.

Theoretical and actual chemical analysis of this product conform to the values reported in Table I.

TABLE I.ANALYSIS Theoretical percent Actual percent Element Concentration,

20.0 25.0 3.05 30.0 3.10 35.0 (super-saturated solution) 3.10

Indium fluorogermanate, In (GeF has been characterized according to the conventional Hull-Debye- Scherrer X-ray diffraction powder technique in order to produce a film record. Exposures were made using a standard X-ray diffraction camera (diameter 114.6 mm.) for four hours at 34 kv. and 18 ma. with a copper target and nickel filter. As is well known to one skilled in the art, the technique causes all chemical compounds to diffract X-rays according to a pattern specific for each compound. The X-rays expose a film according to a specific pattern, which appears on the film as characteristic lines, the interplanar spacing and the relative intensity of which may be measured in order to identify the compound. For comparative purposes, corresponding values were obtained for (NH GeF InCl and NH Cl. The pattern for In (GeF is distinctive and distinguishes this compound from the other compounds evaluated.

4 ORAL COMPOSITIONS COMPRISING INDIUM FLUOROGERMANATE The compound of this invention may be applied to the teeth in simple aqueous solution form (as in a topical treatment or in the form of an aqueous mouthwash; however, it is also Well suited for use in other oral compositions for caries prophylaxis which contain one or more ionically compatible adjuvants. In general, oral compositions produced in accordance with the present invention comprise from about 0.01 to 50% by weight of indium fluorogermanate.

Oral compositions designed for relatively frequent use, such as dentifrices and mouthwashes, will contain lower levels of indium fluorogermanate than compositions which are applied less frequently (e.g., prophylaxis pastes and topical solutions). Thus, dentifrices preferably contain from about 0.1% up to about 1.0% by Weight of indium fluorogermanate, whereas prophylaxis pastes preferably comprise about 10 to 30% indium fluorogermanate by weight and aqueous topical solutions preferably comprise about 5 to 40% indium fluorogermanate by weight.

The cleaning and polishing material in dentifrices of this invention can comprise from about 20 to by Weight of the total composition. Preferably, toothpastes contain from 20 to 60% cleaning and polishing agent by weight, and toothpowders contain from 60 to 95% by weight. Examples of suitable cleaning and polishing agents suitable for use in a dentifrice include, without limitation, calcium pyrophosphate, Ca P O calcium hydrogen phosphate dihydrate, CaHPO' -2H O; anhydrous calcium hydrogen phosphate, CaHPO insoluble sodium metaphosphate, (NaPO calcium carbonate, CaCO melamine formaldehyde resins (US. Patent No. 3,070,- 510); and preferably zirconium silicate and mixtures of zirconium silicate with other cleaning and polishing agents, as set forth and described in applicants co-pending United States patent application, Ser. No. 673,283, filed Oct. 6, 1967. Mixtures of these cleaning and polishing agents may also be used.

Toothpastes require a binder substance to impart desired texture properties. Natural gum binders such as gum tragacanth, gum karaya, gum arabic, etc., and seaweed derivitives such as Irish moss, and alginates, and Water soluble cellulose derivitives, such as hydroxyethyl cellulose and sodium carboxymethyl cellulose, can be used for this purpose. Desirably those materials are employed which are most compatible with the fluoride ion. Binders which have no ionic groups, such as hydroxyethyl cellulose, are especially preferred. Improvements in texture can also be attained by including an additional material such as colloidal magnesium aluminum silicate.

Thickening agents in an amount of from 0.5% to 5.0% by weight can be used to form a satisfactory toothpaste.

Toothpaste conventionally contains sudsing agents. Suitable sudsing agents include, but are not limited to, water-soluble alkyl sulfates having from 8 to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulfate, water-soluble salts of sulfonated monoglycerides, fatty acids having from 10 to 18 carbon atoms in the alkyl radical such as sodium coconut monoglyceride sulfonate, salts of the fatty acid amides of taurines such as sodium- N-methyl palmitoyl tauride, and salts of fatty esters of isethionic acid.

Sudsing agents can be used in the compositions of this invention in the amount from about 0.5 to about 5.0% by weight of the total composition.

It is also desirable to include some humectant material in toothpaste to keep it from hardening. Materials commonly used for this purpose include glycerine, sorbitol and other polyhydric alcohols. Humectants can comprise up to 35% of the toothpaste composition.

Flavoring materials may be included in the toothpaste An exemplary dentifrice formulation is given in the following example.

EXAMPLE I Constituent: Percent by weight Indium fiuorogermanate, 0.20 Zirconium silicate 40.00 Sorbitol 20.00 Glycerine 10.00 Sodium carboxymethyl cellulose 1.08 Sodium coconut monoglyceride sulfonate 0.81 Sodium lauryl sulfate 0.70 Flavor and minor ingredients 1.84 Distilled water Balance Constituent: Percent by weight Indium fluorogermanate Zirconium silicate 55 Liquids (water, binders, minor ingredients) Aqueous mouthwashes containing the indium fluorogermanate salts constitute another preferred embodiment of this invention. An exemplary mouthwash composition is given in the following example.

EXAMPLE III Constituent: Percent by weight Indium fluorogermanate 0.07 Ethyl alcohol (50% aqueous) 86.43 Flavoring 5.0 Sodium lauryl sulfate 7.5 Acetic acid 1.0

ANTICARIOGENIC EFFECTIVENESS The anticariogenic effectiveness of indium fiuorogermanate may be demonstrated by the dental caries experience of rats (standard experimental animals for anticariogenic studies). The effect of various dentifrice compositions in reducing the solubility of dental enamel in acid is a reliable indicator of anticariogenicity. Enamel solubility characteristics of dental compositions can be determined by a number of tests well known in the art. The particular test for reduction in tooth enamel solubility described herein comprises a comparison of acid solubility of a given tooth before and after treatment with the given test composition. The said comparison is expressed as ESR, that is, enamel solubility reduction.

The standard one-day test procedure to determine rat tooth ESR in vivo is as follows. The teeth of a group of suitably selected test rats were brushed three times in a four-hour period using various fluoride and non-fluoride containing dentifrice compositions. One hour after the last brushing the animals were sacrificed by chloroform inhalation. Each mandibular hemijaw was removed, then the clinical crowns of each were decalcified in 0.2 N (pH 4.0) sodium acetate buffer for twenty minutes. The decalcification solutions were then analyzed for phosphorus by a colorimetric method (Fisk and Subbarow, The Colorimetric Determination of Phosphorus, J. Bio. Chem., 662375, 1925). Phosphorus liberation of the teeth brushed with various dentifrice compositions was compared to a non-fluoride containing control, and the results of such comparison are reported as a percentage reduction of enamel solubility (i.e., ESR). I

The effect of several fluoride-phosphate dentifrices upon enamel solubility in rats was determined by tests utilizing the standard one-day procedure described above. A suitable number of test rats were divided into a number of groups. Dentifrices were specially prepared utilizing various abrasive, fluoride, and phosphate ingredients. The abrasive compounds used in these specially prepared dentifrices were a combination of ZrSiO -talc (1:3), Ca P O and talc containing a minor amount of tremolite as an impurity. Indium fiuorogermanate, In (GeF was the fluoride compound used in these dentifrices. These dentifrices were compared to a non-fluoride calcium pyrophosphate control dentifrice and to a commercially available stannous fluoride calcium pyrophosphate-containing dentifrice with the balance of the various dentifrices being essential equivalents. Table III reports the ESR data for each dentifrice tested. These data show that indium fluorogermanate possesses substantial anticariogenic effectiveness when compared to the control dentifrice and to the commercially available stannous fluoride calcium pyrophosphate containing dentifrice.

TABLE III Dentilrice constituents (percent by wt.)

ESR data, Fluoride mean conc. percent Abrasive system Fluoride (percent) reduction C32P201- SnF2 0. 4 22. 0

(394F207- II12( G8Fa)a 0. 2 49. 3

ZrSiOutalc (1:3 wt. IIl2(GeF6)s 0. 2 45. 4

mixture).

Mg3Si4Oi (OH)2* In (GeF) 0. 2 30. 6

*Contains 18% tremolite as an impurity.

Additional tests have been performed utilizing the standard one-day procedure described above. All dentifrices utilized in this test contained Ca P O as the abra- 1 An ammonium salt of a condensation product of ammonia, NHe, and phosphorous pentoxide, P4010, as set forth and tieseribed in US. Patent No. 2,122,122 and commercially available under the Victamide name from the Stauffer Chemical Company.

7 TOXICITY In addition to exhibiting a high level of anticariogenic activity, indium fluorogermanate exhibits a low toxicity, comparing quite favorably in this regard to other anticariogenic fluorides as shown by the following experimental studies.

The toxicity of indium fluorogermanate has been determined in mice (standard experimental animals for this purpose). A total of 191 mice weighing between 15 and 25 g. each were given various concentrations of indium fluorogermanate by means of a stomach tube. The results of this study are reported in Table V, and these data indicate that the oral LD (the concentration at which there is a 50% mortality rate) for indium fluorogermanate in mice is approximately 85 mg. fluoride per kg. of body weight. In comparison, the LD for NaF has been determined to be approximately 36 mg. F/kg. Thus, the results indicate that the exemplary indium fluorogermanate salts are comparable or superior to known fluorides.

TABLE V In2(GeFu)a concentration Initial Number (mg. F per kg. number of animals dead Percent body weight) animals in 24 hours mortality 3 0. 0 3 0 0.0 10 0 0. 0 10 1 l0. 0 13 3 23.1 23 2 8. 7 10 50. O 41 30 73. 2 46 a4 13. 9 23 18 78. '3 3 2 66. 7 3 3 100. 0 3 3 100.0

Animal studies further reveal that indium fluorogermanate, when topically applied, does not damage the gingival tissues of the test animals. Young animals consisting of 100-200 g. rats or 100 g. hamsters were divided into appropriate groups. Test compositions containing in concentrations sufficient to provide 1,000 p.p.m. fluoride in either an aqueous solution or dentifrice form were prepared. The solutions were topically placed by applicators gently in the vestibule near the mandibular molars for 30 seconds; and the dentrifrices were applied either "by a toothbrush or cotton applicators directly to the mandibular molar area for 30 seconds. The animals received treatments for predetermined intervals, and were then sacrificed either one hour or 24 hours following the final treatment. The oral tissue (mucosa and supporting structures) were surgically removed and prepared in the normal manner for histologic examination. Examination of the oral tissue revealed that there was not any detectable change in the gingival tissue.

While the present invention has been described herein with reference to certain exemplary embodiments thereof, it should be understood that various changes, modifications, and alterations may be efiected in the materials utilized, in the proportions of materials, and in the manner of formulation without departing from the spirit andthe scope of the present invention, as defined in the appended claim.

I claim:

1. Indium fiuorogermanate, In (GeF References Cited UNITED STATES PATENTS 3,441,371 4/ 1969 Muhler 23-51 OTHER REFERENCES Gebala et al.: Journal of Inorganic and Nuclear Chemistry, vol. 29, September 1967, pp. 2301-2305.

Hoppe: Journal of Inorganic and Nuclear Chemistry, vol. 8, 1958, pp. 437-438.

Johnson: Chemical Reviews, vol. 51, 1952, pp. 442, 443 and 462 of interest.

HERBERT T. CARTER, Primary Examiner U.S. Cl. X.R. 

